Hypoxemia, ischemia and increased intracranial pressure are associated with many assaults on the brain, including severe head injury, thrombosis, and cerebral hemorrhage. Since the brain has limited reserves of high energy adenyl nucleotides, any condition that results in cerebral ischemia or hypoxia can impair aerobic oxidative metabolism and development of anaerobic glycolysis. Head injury or severe hypoxia can also lead to production of injurious amounts of lactic acid. Moreover, phosphofructokinase (PFK), the rate-limiting enzyme responsible for the conversion of fructose-6 phosphate to fructose 1,6-diphosphate (FDP), can be inhibited during anaerobic glycolysis due to the development of cellular acidosis. The resulting condition is one of rapid decline of intracellular adenosine triphosphate (ATP), the major source of cellular energy. Deterioration of the cerebral energy state can also result in the loss of intracellular K.sup.+ while promoting intracellular free Ca.sup.2+ during depolarization of the neuronal membrane. Experimental evidence has implicated intracellular Ca.sup.2+ accumulation to a chain of biochemical events leading to irreversible neuronal death. Those events include the uncoupling of oxidative phosphorylation, activation of intracellular enzymes and generation of cell-damaging hydroxyl or oxygen free radicals.
Previous experimental studies have shown that intravenous FDP can improve electrical brain activity and protect cerebral neurons from damage following ischemic injury in rabbits. A number of studies indicate that FDP is useful in improving brain metabolism following ischemia and hypoglycemic coma, ostensibly by increasing intracellular ATP levels and preventing intracellular Ca.sup.2+ accumulation. FDP appears useful in cardiogenic shock, intestinal ischemia, myocardial infarction or ischemia, renal ischemia, hypoglycemic coma, acute respiratory distress syndrome, liver ischemia and injury, hemorrhagic shock, peritonitis, cardiomyopathy, cardiac arrhythmias and doxorubicin-induced cardiotoxicity. FDP reduced endotoxin shock by preventing intestinal fluid loss, restoring mean arterial pressure and preserving urinary output. One study, however, failed to confirm a benefit by FDP in myocardial ischemia. In many of the studies a consensus opinion is that FDP appears as an ideal agent to increase energy production during anaerobic glycolysis and to reduce the formation of oxygen radicals. Although FDP is a phosphorylated sugar, it crosses the blood-brain barrier and enters the neurons. Theoretically, one mole of FDP yields four moles of ATP whereas one mole of glucose yields only two moles of ATP. In order to produce usable energy from FDP, large quantities of the compound must be administered. FDP has also been shown beneficial in patients with traumatic shock following spinal cord injury, gun-shot wounds to the neck, chest and abdomen, head injury, and duodenal rupture.
The use of dimethyl sulfoxide (DMSO) following cerebral trauma or ischemia is reported to protect cell membranes, increase cerebral blood flow, reduce hydroxyl radical formation, inhibit platelet aggregation and significantly lower elevated intracranial pressure. In monkeys, DMSO has also been shown to be effective after high missile brain injury by improving mean arterial pressure, cerebral perfusion pressure, and cerebral metabolic rate of oxygen. Furthermore, DMSO reduces the cerebral metabolic rate of lactate. The metabolism of lactate can lead to lactic acidosis and eventual impairment of oxidative phosphorylation with decreased production of ATP. For these reasons, use of DMSO to protect brain tissue after vascular and physical insults has been suggested.
DMSO has been shown in numerous experimental studies to reduce intracranial pressure elevation, inhibit platelet aggregation, reduce edema after focal brain ischemia, increase survival after stroke and gun-shot wound to the head. Additionally, it has been reported that DMSO can protect glial cells against sonic damage, increase cerebral and spinal cord blood flow following trauma or ischemia, protect tissue from radiation and cold-induced damage, prevent ischemic damage to the kidney, intestines and brain, improve neurologic outcome after spinal and head trauma and inhibit platelet aggregation in obstructed coronary vessels. Clinical studies have shown that DMSO can improve end-stage acute respiratory distress syndrome and, when given to patients intravenously, can reduce intracranial pressure following severe closed head injury, increase cerebral blood flow following cerebral hemorrhage, reduce amyloid deposition in patients with primary amyloidosis, and improve mitochondrial function and energy metabolism partly due to DMSO's action as a free radical scavenger. DMSO has been shown useful in the treatment of reflex sympathetic dystrophy secondary to inflammatory reactions. DMSO is reported to have important biological activity in reducing conduction of painful stimuli through C-fibers and may have anti-carcinogenic, anti-viral action.
No previous suggestion has been seen that use of dimethylsulfoxide with fructose 1,6-diphosphate would be advantageous. It was not previously known that DMSO and FDP would act synergistically in preventing damage to neuronal tissue.